Rheumatoid arthritis (RA) patients differ considerably in their clinical course and in response to treatment (1; 2). Despite the fact that studies are supporting combination therapy to optimally suppress disease activity, most newly diagnosed patients start with monotherapy, with the antifolate methotrexate (MTX) being the preferred disease-modifying antirheumatic drug (DMARD) (3-6).
Randomized controlled clinical trials provide evidence that methotrexate alters the clinical course, although only about 40% of the patients show good clinical response (7-9). On the other hand, lack of response is associated with progression of joint damage and functional decline (6; 10; 11). However, it is not possible to predict which patients will respond since most studies concerning methotrexate efficacy have not investigated the predictors for response. Clear predictors for response to methotrexate will contribute to the allocation of effective therapy and will establish the reduction of disease activity and limit functional decline.
In candidate gene driven pharmacogenetic studies, polymorphisms in genes coding for proteins involved in pharmacokinetic or pharmacodynamic pathways related to the drug under study are selected and tested for associations with treatment outcome (12-14). For methotrexate, several studies showed that single nucleotide polymorphisms in genes coding for the folate pathway enzymes are associated with treatment response (15-17). Although methotrexate may act in rheumatoid arthritis through inhibition of folate pathway enzymes, more recent reports indicate that its response may also be related to the release of endogenous anti-inflammatory adenosine (18; 19). Studies concerning other complex traits have indicated the relevance of polymorphisms in genes coding for enzymes related to adenosine release for clinical outcome (15; 20-24). The current invention demonstrates for the first time that genetic variants in these genes are associated with methotrexate treatment outcome and exploits these associations for methods of diagnostics and treatment.